Chromatin accessibility landscape and developmental regulatory network reveal cis-regulatory elements and toolkit transcription factors of rumen origin

The innovation of rumen organ with functional complexity and unique traits is a fundamental question in evolutionary biology. Previous comparative genomics and transcriptomic studies revealed 221,166 ruminant-specific conserved non-coding DNA elements (RSCNE) and 656 rumen specifically expressed genes (RSEG). Here, we generate time series of paired ATAC-seq and RNA-seq data during rumen and esophagus development in sheep and reconstruct gene regulatory network to understand how the transcription factors (TF) regulate genes via batteries of RSCNEs, which over development, lead to the cell type specific activation of RSEGs. We developed an evolutionary Conserved Non-coding Element interpretation method by Gene Regulatory Network (cneGRN) to integrate comparative genomics, comparative transcriptomic, and multi-omics data. A genome-wide developmental gene regulatory network not only presents the global picture how rumen recruits gene expression from other tissues by activating RSCNEs to achieve many traits, but also identifies cis-regulatory elements and toolkit TFs which are validated by in vitro experiments. Collectively, we demonstrated a systematic approach to understand the large-scale maps of conserved noncoding elements by modeling multi-omics data over development for its act on gene regulation. Our method allows EvoDevo thinking in how gene regulation could evolve and shape animal evolution.